Li Y, Klena NT, Gabriel GC, Liu X, Kim AJ, Lemke K, Chen Y, Chatterjee B, Devine W, Damerla RR, Chang C, Yagi H, San Agustin JT, Thahir M, Anderton S, Lawhead C, Vescovi A, Pratt H, Morgan J, Haynes L, Smith CL, Eppig JT, Reinholdt L, Francis R, Leatherbury L, Ganapathiraju MK, Tobita K, Pazour GJ, Lo CW.
Nature. 2015 May 28;521(7553):520-4. doi: 10.1038/nature14269. Epub 2015 Mar 25.
Select item 26033645
Comment from Dr. Ginnie Abarbanell (Atlanta), section editor of Fetal Cardiology Journal Watch: This is a study of genetically altered mice [InbredC57BL/6Jmice mutagenized with ethylnitrosourea(ENU)] bred to recover recessive coding mutations for the purpose of evaluating the presence of congenital heart disease (CHD) and related genes. Fetal echocardiograms were done on 87,355 mice to identify fetal mice with CHD. The CHD diagnoses were then confirmed using micro-computed tomography (CT)/ micro-magnetic resonance imaging (MRI), necropsy and histopathology. 218 CHD mouse models were recovered. Whole-exome sequencing identified 91 recessive CHD mutations in 61 genes. This included 34 cilia-related genes, 16 genes involved in cilia-transduced cell signaling, and 10 genes regulating vesicular trafficking, a pathway important for ciliogenesis and cell signaling. These findings suggest that cilia and cilia transduced cell signaling have an important role in pathogenesis of CHD.
Take home points:
- Cilia and cilia transduced cell signaling are important in the pathogenesis of CHD
- These researchers were able to obtain impressive ultrasound and CT/MRI images of the fetal mouse heart. See illustrations below.
- Cardiac genetics is complex and as more discoveries are made the details become more intricate. See diagram of gene networks below.
Schellen C, Schwartz E, Gruber GM, Mlczoch E, Weber M, Ulm B, Brugger PC, Langs G, Salzer-Muhar U, Prayer D, Kasprian G.
Am J Obstet Gynecol. 2015 May 22. pii: S0002-9378(15)00522-0. doi: 10.1016/j.ajog.2015.05.046. [Epub ahead of print]
Select item 26007205
Comment from Dr. Ginnie Abarbanell (Atlanta), section editor of Fetal Cardiology Journal Watch: Fetal brain MRIs were done on fetuses (n=24) with a prenatal diagnosis of Tetralogy of Fallot (TOF) and compared to age-matched control fetuses (n=24). Fetal MRIs were performed on the TOF group at a median of 25 weeks gestation age. Total brain volume, gray matter volume and subcortical brain volume were found to be decreased in those fetuses with TOF. Interestingly, the intracranial and cerebellar volumes was not reduced in fetuses with TOF compared to controls. These findings suggest that TOF impacts brain development at a very early stage.
Take home points:
- This fetal MRI study demonstrates early changes in the fetal brain with TOF. These finding are consistent with the hypothesis that neurodevelopmental deficits in children with congenital heart disease (CHD) are at least in part secondary to differences in fetal brain development.
Hill GD, Block JR, Tanem JB, Frommelt MA.
Prenat Diagn. 2015 May 19. doi: 10.1002/pd.4622. [Epub ahead of print]
Select item 25982591
Comment from Dr. Ginnie Abarbanell (Atlanta), section editor of Fetal Cardiology Journal Watch: Several studies have demonstrated improved outcomes in infants in whom a prenatal diagnosis of congenital (CHD) was available prior to delivery to aid in planning of delivery and postnatal care. This study evaluated a cohort of 535 infants born between 2007 and 2013 with CHD. The overall prenatal diagnosis rate was 61% and had improved from 44% in 2007 to 69% in 2013. Risk factors identified with missed prenatal diagnosis were (1) a lesion that required a view other than a four chamber view to make the diagnosis, (2) absence of another organ system anomaly, and (3) living in a higher poverty or lower population density (rural) communities. Prenatal detection rate was highest in tricuspid atresia and lowest in total anomalous pulmonary venous connection. Researches found that “Lesions such as aortic stenosis, double outlet right ventricle, pulmonary atresia, tetralogy of Fallot, transposition of the great arteries, and truncus arteriosus, which require an outflow tract view, and coarctation of the aorta, interrupted aortic arch, and total anomalous pulmonary venous return, which require an aortic arch view or color and spectral Doppler imaging, were less commonly identified in rural communities.” The authors conclude “Our data suggest that training programs in detection of CHD by screening obstetric ultrasound should be targeted to these impoverished, rural communities for the greatest impact.”
Take home points:
- Prenatal diagnosis of CHD has improved.
- There is still room for improvement with education regarding identification of CHD not classically seen on the 4 chamber cardiac view especially in more rural areas where maternal fetal medicine specialists are less prevalent.
Koshy T, Venkatesan V, Perumal V, Hegde S, Paul SF.
Pediatr Cardiol. 2015 May 17. [Epub ahead of print]
Select item 25981562
Comment from Dr. Shaji Menon (Salt Lake City, UT), section editor of Pediatric Cardiology Journal Watch: Conotruncal heart defects (CTHDs), accounts for 10–15 % of congenital heart diseases (CHD). This defects involve cardiac structures that are partially derived from cell lineages such as the cardiac neural crest cells and the secondary heart field. Prenatal use of folic acid has been reported to a reduced risk of CHDs and neural tube defects (NTD). Single nucleotide polymorphisms (SNPs) in the genes controlling folate metabolism has been associated with CHDs. Methylenetetrahydrofolate reductase (MTHFR), plays a central role in folate metabolism. The objective of this case-control study was to devaluate the association of six selected folate-metabolizing gene polymorphisms with the risk of non-syndromic CTHDs in an Indian population. The findings of this study shows that 5, 10-methylenetetrahydrofolate (MTHFR) A1298C polymorphism, the CC variant homozygote genotype was associated with a significantly increased risk of CTHDs in Indian population. This study builds on the existing evidence of role of folate metabolism in cardiovascular development and possibility of using folic acid supplementation in reducing the incidence of CHDs.
Mlczoch E, Hanslik A, Luckner D, Kitzmüller E, Prayer D, Michel-Behnke I.
Ultrasound Obstet Gynecol. 2015 May;45(5):618-21. doi: 10.1002/uog.13434.
Comment from Dr. Shaji Menon (Salt Lake City, UT), section editor of Pediatric Cardiology Journal Watch: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by abnormal cell proliferation and tumor growth in a number of organ systems, including brain, kidneys, skin, liver, eyes and heart. Causative mutations can occur in either the TSC1 gene on chromosome 9q34 (hamartin) or the TSC2 gene on chromosome 16p13.3 (tuberin). Mutations in these two genes can lead to up regulation of mTOR complex 1, resulting in abnormal cell proliferation, cell growth and protein synthesis. Cardiac rabdomyoma are often diagnosed prenatally and the rabdomyoma growth is mainly during the second and third trimesters, continuing until the early postnatal period, followed by regression during the first year of postnatal life. In majority, the standard of care is observation until spontaneous regression. However, in rare cases of large rabdomyomas causing hemodynamic compromise secondary to mechanical obstruction, surgical intervention may be required. This case report describes rapid involution of a prenatally diagnosed giant rabdomyoma causing right ventricular outflow tract obstruction following postnatal treatment with the mTOR inhibitor everolimus. This report and similar previous reports provides us with a novel and promising therapeutic approaches with mTOR inhibitors in patients with TSC diagnosed with large cardiac rhabdomyomas.